The eukaryote genome constantly faces the threat of damage from exogenous and endogenous mutagens. Mammalian cells, therefore, have evolved an intricate network of defenses to maintain genomic stability. p53 is at the crossroads of these defense pathways. We investigate rare genomic instability and/or premature aging diseases, e.g., Bloom, Werner, Rothmund-Thomson, and Li-Fraumeni Syndromes, to gain insight into p53 function in the general population. For example, p53 cooperates with the Bloom Syndrome helicase, BLM, and the prorecombinogenic Rad51 during DNA replicative stress to act as a molecular governor of DNA recombination. We have also discovered transcriptional cofactors of p53, i.e., ING2-5, that enhance p53 effector functions in cell cycle checkpoints, apoptosis, and senescence. We plan to continue studying p53-mediated replicative senescence modulated by either ING family proteins or by POT1 and WRN that govern telomere attrition.